Advertisement

Current Diabetes Reports

, 19:102 | Cite as

Pharmacological Modulation of Ghrelin to Induce Weight Loss: Successes and Challenges

  • Martha A. Schalla
  • Andreas StengelEmail author
Obesity (KM Gadde, Section Editor)
  • 25 Downloads
Part of the following topical collections:
  1. Topical Collection on Obesity

Abstract

Purpose of Review

Obesity is affecting over 600 million adults worldwide and has numerous negative effects on health. Since ghrelin positively regulates food intake and body weight, targeting its signaling to induce weight loss under conditions of obesity seems promising. Thus, the present work reviews and discusses different possibilities to alter ghrelin signaling.

Recent Findings

Ghrelin signaling can be altered by RNA Spiegelmers, GHSR/Fc, ghrelin-O-acyltransferase inhibitors as well as antagonists, and inverse agonists of the ghrelin receptor. PF-05190457 is the first inverse agonist of the ghrelin receptor tested in humans shown to inhibit growth hormone secretion, gastric emptying, and reduce postprandial glucose levels. Effects on body weight were not examined.

Summary

Although various highly promising agents targeting ghrelin signaling exist, so far, they were mostly only tested in vitro or in animal models. Further research in humans is thus needed to further assess the effects of ghrelin antagonism on body weight especially under conditions of obesity.

Keywords

Antagonist Ghrelin-O-acyl transferase GOAT Growth hormone Inverse agonist Obesity 

Abbreviations

ACTH

Adrenocorticotropic hormone

AZ-GHS-22

Non-CNS penetrant inverse agonist 22

AZ-GHS-38

CNS penetrant inverse agonist 38

BMI

Body mass index

CpdB

Compound B

CpdD

Compound D

DIO

Diet-induced obesity

GH

Growth hormone

GHRP-2

Growth hormone–releasing peptide-2

GHRP-6

Growth hormone–releasing peptide 6

GHSR

Growth hormone secretagogue receptor

GOAT

Ghrelin-O-acyltransferase

GRLN-R

Ghrelin receptor

icv

Intracerebroventricular

POMC

Proopiomelanocortin

sc

Subcutaneous

SPM

RNA Spiegelmer

WHO

World Health Organization.

Notes

Author Contributions

M.S. wrote the first draft of the paper, and A.S. thoroughly reviewed the manuscript; both authors finalized the manuscript.

Funding Information

This work was supported by funding of the German Research Foundation (STE 1765/3-2) and Charité University Funding (UFF 89/441-176, A.S.).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    World Health Organization. Obesity and Overweigth. 2018. https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight. Accessed 1 June 2019.
  2. 2.
    Klok MD, Jakobsdottir S, Drent ML. The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review. Obes Rev. 2007;8(1):21–34.  https://doi.org/10.1111/j.1467-789X.2006.00270.x.CrossRefPubMedGoogle Scholar
  3. 3.
    Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402(6762):656–60.  https://doi.org/10.1038/45230.CrossRefPubMedGoogle Scholar
  4. 4.
    Davenport AP, Bonner TI, Foord SM, Harmar AJ, Neubig RR, Pin JP, et al. LVI. Ghrelin receptor nomenclature, distribution, and function. Pharmacol Rev. 2005;57(4):541–6.  https://doi.org/10.1124/pr.57.4.1.CrossRefPubMedGoogle Scholar
  5. 5.
    Ariyasu H, Takaya K, Tagami T, Ogawa Y, Hosoda K, Akamizu T, et al. Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans. J Clin Endocrinol Metab. 2001;86(10):4753–8.  https://doi.org/10.1210/jcem.86.10.7885.CrossRefPubMedGoogle Scholar
  6. 6.
    Date Y, Nakazato M, Hashiguchi S, Dezaki K, Mondal MS, Hosoda H, et al. Ghrelin is present in pancreatic alpha-cells of humans and rats and stimulates insulin secretion. Diabetes. 2002;51(1):124–9.CrossRefGoogle Scholar
  7. 7.
    Gnanapavan S, Kola B, Bustin SA, Morris DG, McGee P, Fairclough P, et al. The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans. J Clin Endocrinol Metab. 2002;87(6):2988.  https://doi.org/10.1210/jcem.87.6.8739.CrossRefPubMedGoogle Scholar
  8. 8.
    Barreiro ML, Gaytán F, Caminos JE, Pinilla L, Casanueva FF, Aguilar E, et al. Cellular location and hormonal regulation of ghrelin expression in rat testis. Biol Reprod. 2002;67(6):1768–76.  https://doi.org/10.1095/biolreprod.102.006965.CrossRefPubMedGoogle Scholar
  9. 9.
    Kojima M, Hamamoto A, Sato T. Ghrelin O-acyltransferase (GOAT), a specific enzyme that modifies ghrelin with a medium-chain fatty acid. J Biochem. 2016;160(4):189–94.  https://doi.org/10.1093/jb/mvw046.CrossRefPubMedGoogle Scholar
  10. 10.
    Gutierrez JA, Solenberg PJ, Perkins DR, Willency JA, Knierman MD, Jin Z, et al. Ghrelin octanoylation mediated by an orphan lipid transferase. Proc Natl Acad Sci U S A. 2008;105(17):6320–5.  https://doi.org/10.1073/pnas.0800708105.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Yang J, Brown MS, Liang G, Grishin NV, Goldstein JL. Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone. Cell. 2008;132(3):387–96.  https://doi.org/10.1016/j.cell.2008.01.017.CrossRefPubMedGoogle Scholar
  12. 12.
    Sakata I, Yang J, Lee CE, Osborne-Lawrence S, Rovinsky SA, Elmquist JK, et al. Colocalization of ghrelin O-acyltransferase and ghrelin in gastric mucosal cells. Am J Physiol Endocrinol Metab. 2009;297(1):E134–41.  https://doi.org/10.1152/ajpendo.90859.2008.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Stengel A, Goebel M, Wang L, Tache Y, Sachs G, Lambrecht NW. Differential distribution of ghrelin-O-acyltransferase (GOAT) immunoreactive cells in the mouse and rat gastric oxyntic mucosa. Biochem Biophys Res Commun. 2010;392(1):67–71.  https://doi.org/10.1016/j.bbrc.2009.12.169.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Weibert E, Stengel A. The X/A-like cell revisited - spotlight on the peripheral effects of NUCB2/nesfatin-1 and ghrelin. J Physiol Pharmacol. 2017;68(4):497–520.PubMedGoogle Scholar
  15. 15.
    Guan XM, Yu H, Palyha OC, McKee KK, Feighner SD, Sirinathsinghji DJ, et al. Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues. Brain Res Mol Brain Res. 1997;48(1):23–9.CrossRefGoogle Scholar
  16. 16.
    Tschop M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Nature. 2000;407(6806):908–13.  https://doi.org/10.1038/35038090.CrossRefPubMedGoogle Scholar
  17. 17.
    Theander-Carrillo C, Wiedmer P, Cettour-Rose P, Nogueiras R, Perez-Tilve D, Pfluger P, et al. Ghrelin action in the brain controls adipocyte metabolism. J Clin Invest. 2006;116(7):1983–93.  https://doi.org/10.1172/jci25811.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Davies JS, Kotokorpi P, Eccles SR, Barnes SK, Tokarczuk PF, Allen SK, et al. Ghrelin induces abdominal obesity via GHS-R-dependent lipid retention. Mol Endocrinol (Baltimore, Md). 2009;23(6):914–24.  https://doi.org/10.1210/me.2008-0432.CrossRefGoogle Scholar
  19. 19.
    Rodriguez A, Gomez-Ambrosi J, Catalan V, Gil MJ, Becerril S, Sainz N, et al. Acylated and desacyl ghrelin stimulate lipid accumulation in human visceral adipocytes. Int J Obes (2005). 2009;33(5):541–52.  https://doi.org/10.1038/ijo.2009.40.CrossRefGoogle Scholar
  20. 20.
    Briggs DI, Enriori PJ, Lemus MB, Cowley MA, Andrews ZB. Diet-induced obesity causes ghrelin resistance in arcuate NPY/AgRP neurons. Endocrinology. 2010;151(10):4745–55.  https://doi.org/10.1210/en.2010-0556.CrossRefPubMedGoogle Scholar
  21. 21.
    Naznin F, Toshinai K, Waise TMZ, NamKoong C, Md Moin AS, Sakoda H, et al. Diet-induced obesity causes peripheral and central ghrelin resistance by promoting inflammation. J Endocrinol. 2015;226(1):81–92.  https://doi.org/10.1530/JOE-15-0139.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    le Roux CW, Patterson M, Vincent RP, Hunt C, Ghatei MA, Bloom SR. Postprandial plasma ghrelin is suppressed proportional to meal calorie content in normal-weight but not obese subjects. J Clin Endocrinol Metab. 2005;90(2):1068–71.  https://doi.org/10.1210/jc.2004-1216.CrossRefPubMedGoogle Scholar
  23. 23.
    Onnerfalt J, Erlanson-Albertsson C, Montelius C, Thorngren-Jerneck K. Obese children aged 4–6 displayed decreased fasting and postprandial ghrelin levels in response to a test meal. Acta Paediatrica (1992). 2018;107(3):523–8.  https://doi.org/10.1111/apa.14165.CrossRefGoogle Scholar
  24. 24.
    Wren AM, Seal LJ, Cohen MA, Brynes AE, Frost GS, Murphy KG, et al. Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab. 2001;86(12):5992.  https://doi.org/10.1210/jcem.86.12.8111.CrossRefPubMedGoogle Scholar
  25. 25.
    Venkova K, Mann W, Nelson R, Greenwood-Van MB. Efficacy of ipamorelin, a novel ghrelin mimetic, in a rodent model of postoperative ileus. J Pharmacol Exp Ther. 2009;329(3):1110–6.  https://doi.org/10.1124/jpet.108.149211.CrossRefPubMedGoogle Scholar
  26. 26.
    Hansen BS, Raun K, Nielsen KK, Johansen PB, Hansen TK, Peschke B, et al. Pharmacological characterisation of a new oral GH secretagogue, NN703. Eur J Endocrinol. 1999;141(2):180–9.CrossRefGoogle Scholar
  27. 27.
    Kuriyama H, Hotta M, Wakabayashi I, Shibasaki T. A 6-day intracerebroventricular infusion of the growth hormone-releasing peptide KP-102 stimulates food intake in both non-stressed and intermittently-stressed rats. Neurosci Lett. 2000;282(1–2):109–12.CrossRefGoogle Scholar
  28. 28.
    Laferrere B, Abraham C, Russell CD, Bowers CY. Growth hormone releasing peptide-2 (GHRP-2), like ghrelin, increases food intake in healthy men. J Clin Endocrinol Metab. 2005;90(2):611–4.  https://doi.org/10.1210/jc.2004-1719.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Mericq V, Cassorla F, Bowers CY, Avila A, Gonen B, Merriam GR. Changes in appetite and body weight in response to long-term oral administration of the ghrelin agonist GHRP-2 in growth hormone deficient children. J Ped Endocrinol Metab. 2003;16(7):981–5.CrossRefGoogle Scholar
  30. 30.
    Garcia JM, Polvino WJ. Pharmacodynamic hormonal effects of anamorelin, a novel oral ghrelin mimetic and growth hormone secretagogue in healthy volunteers. Growth Hormon IGF Res. 2009;19(3):267–73.  https://doi.org/10.1016/j.ghir.2008.12.003.CrossRefGoogle Scholar
  31. 31.
    Garcia JM, Friend J, Allen S. Therapeutic potential of anamorelin, a novel, oral ghrelin mimetic, in patients with cancer-related cachexia: a multicenter, randomized, double-blind, crossover, pilot study. Supp Care Cancer. 2013;21(1):129–37.  https://doi.org/10.1007/s00520-012-1500-1.CrossRefGoogle Scholar
  32. 32.
    Garcia JM, Polvino WJ. Effect on body weight and safety of RC-1291, a novel, orally available ghrelin mimetic and growth hormone secretagogue: results of a phase I, randomized, placebo-controlled, multiple-dose study in healthy volunteers. Oncologist. 2007;12(5):594–600.  https://doi.org/10.1634/theoncologist.12-5-594.CrossRefPubMedGoogle Scholar
  33. 33.
    Zollers B, Rhodes L, Heinen E. Capromorelin oral solution (ENTYCE(R)) increases food consumption and body weight when administered for 4 consecutive days to healthy adult Beagle dogs in a randomized, masked, placebo controlled study. BMC Vet Res. 2017;13(1):10.  https://doi.org/10.1186/s12917-016-0925-z.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Fraser GL, Hoveyda HR, Tannenbaum GS. Pharmacological demarcation of the growth hormone, gut motility and feeding effects of ghrelin using a novel ghrelin receptor agonist. Endocrinology. 2008;149(12):6280–8.  https://doi.org/10.1210/en.2008-0804.CrossRefPubMedGoogle Scholar
  35. 35.
    Hassouna R, Labarthe A, Zizzari P, Videau C, Culler M, Epelbaum J, et al. Actions of agonists and antagonists of the ghrelin/GHS-R pathway on GH secretion, appetite, and cFos activity. Front Endocrinol. 2013;4:25.  https://doi.org/10.3389/fendo.2013.00025.CrossRefGoogle Scholar
  36. 36.
    Shearman LP, Wang SP, Helmling S, Stribling DS, Mazur P, Ge L, et al. Ghrelin neutralization by a ribonucleic acid-SPM ameliorates obesity in diet-induced obese mice. Endocrinology. 2006;147(3):1517–26.  https://doi.org/10.1210/en.2005-0993.CrossRefPubMedGoogle Scholar
  37. 37.
    Helmling S, Maasch C, Eulberg D, Buchner K, Schroder W, Lange C, et al. Inhibition of ghrelin action in vitro and in vivo by an RNA-Spiegelmer. Proc Natl Acad Sci U S A. 2004;101(36):13174–9.  https://doi.org/10.1073/pnas.0404175101.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Becskei C, Bilik KU, Klussmann S, Jarosch F, Lutz TA, Riediger T. The anti-ghrelin Spiegelmer NOX-B11-3 blocks ghrelin- but not fasting-induced neuronal activation in the hypothalamic arcuate nucleus. J Neuroendocrinol. 2008;20(1):85–92.  https://doi.org/10.1111/j.1365-2826.2007.01619.x.CrossRefPubMedGoogle Scholar
  39. 39.
    Kobelt P, Helmling S, Stengel A, Wlotzka B, Andresen V, Klapp BF, et al. Anti-ghrelin Spiegelmer NOX-B11 inhibits neurostimulatory and orexigenic effects of peripheral ghrelin in rats. Gut. 2006;55(6):788–92.  https://doi.org/10.1136/gut.2004.061010.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Sangiao-Alvarellos S, Helmling S, Vazquez MJ, Klussmann S, Cordido F. Ghrelin neutralization during fasting-refeeding cycle impairs the recuperation of body weight and alters hepatic energy metabolism. Mol Cell Endocrinol. 2011;335(2):177–88.  https://doi.org/10.1016/j.mce.2011.01.010.CrossRefPubMedGoogle Scholar
  41. 41.
    Teubner BJ, Bartness TJ. Anti-ghrelin Spiegelmer inhibits exogenous ghrelin-induced increases in food intake, hoarding, and neural activation, but not food deprivation-induced increases. Am J Physiol Regul Integr Comp Physiol. 2013;305(4):R323–33.  https://doi.org/10.1152/ajpregu.00097.2013.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Gagnon J, Zhu L, Anini Y, Wang Q. Neutralizing circulating ghrelin by expressing a growth hormone secretagogue receptor-based protein protects against high-fat diet-induced obesity in mice. Gene Ther. 2015;22(9):750–7.  https://doi.org/10.1038/gt.2015.38.CrossRefPubMedGoogle Scholar
  43. 43.
    Zorrilla EP, Iwasaki S, Moss JA, Chang J, Otsuji J, Inoue K, et al. Vaccination against weight gain. Proc Natl Acad Sci U S A. 2006;103(35):13226–31.  https://doi.org/10.1073/pnas.0605376103.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Vizcarra JA, Kirby JD, Kim SK, Galyean ML. Active immunization against ghrelin decreases weight gain and alters plasma concentrations of growth hormone in growing pigs. Dom Anim Endocrinol. 2007;33(2):176–89.  https://doi.org/10.1016/j.domaniend.2006.05.005.CrossRefGoogle Scholar
  45. 45.
    Andrade S, Pinho F, Ribeiro AM, Carreira M, Casanueva FF, Roy P, et al. Immunization against active ghrelin using virus-like particles for obesity treatment. Curr Pharm Des. 2013;19(36):6551–8.  https://doi.org/10.2174/13816128113199990506.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Biotechnology C. Phase I/IIa clinical trial with obese individuals shows no effect of CYT009-GhrQb on weight loss. Cytos Biotechnology Press release November 2006;7.Google Scholar
  47. 47.
    Yang J, Zhao TJ, Goldstein JL, Brown MS. Inhibition of ghrelin O-acyltransferase (GOAT) by octanoylated pentapeptides. Proc Natl Acad Sci U S A. 2008;105(31):10750–5.  https://doi.org/10.1073/pnas.0805353105.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Barnett BP, Hwang Y, Taylor MS, Kirchner H, Pfluger PT, Bernard V, et al. Glucose and weight control in mice with a designed ghrelin O-acyltransferase inhibitor. Science. 2010;330(6011):1689–92.  https://doi.org/10.1126/science.1196154.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Teuffel P, Wang L, Prinz P, Goebel-Stengel M, Scharner S, Kobelt P, et al. Treatment with the ghrelin-O-acyltransferase (GOAT) inhibitor GO-CoA-Tat reduces food intake by reducing meal frequency in rats. J Physiol Pharmacol. 2015;66(4):493–503.PubMedGoogle Scholar
  50. 50.
    Rucinski M, Ziolkowska A, Szyszka M, Hochol A, Malendowicz LK. Evidence suggesting that ghrelin O-acyl transferase inhibitor acts at the hypothalamus to inhibit hypothalamo-pituitary-adrenocortical axis function in the rat. Peptides. 2012;35(2):149–59.  https://doi.org/10.1016/j.peptides.2012.04.007.CrossRefPubMedGoogle Scholar
  51. 51.
    • Zhang S, Mao Y, Fan X. Inhibition of ghrelin o-acyltransferase attenuated lipotoxicity by inducing autophagy via AMPK-mTOR pathway. Drug Des Dev Ther. 2018, 873;12:–85.  https://doi.org/10.2147/dddt.s158985. A very recent study identifying the molecular changes induced by GO-CoA-Tat administation.
  52. 52.
    Garner AL, Janda KD. A small molecule antagonist of ghrelin O-acyltransferase (GOAT). Chem Commun. 2011;47(26):7512–4.  https://doi.org/10.1039/c1cc11817j.CrossRefGoogle Scholar
  53. 53.
    Zhao Y, Ma X, Wang Q, Zhou Y, Zhang Y, Wu L, et al. Nesfatin-1 correlates with hypertension in overweight or obese Han Chinese population. Clin Exp Hypertens(1993). 2015;37(1):51–6.  https://doi.org/10.3109/10641963.2014.897722.CrossRefGoogle Scholar
  54. 54.
    McGovern-Gooch KR, Mahajani NS, Garagozzo A, Schramm AJ, Hannah LG, Sieburg MA, et al. Synthetic triterpenoid inhibition of human ghrelin-O-acyltransferase: the involvement of a functionally required cysteine provides mechanistic insight into ghrelin acylation. Biochemistry. 2017;56(7):919–31.  https://doi.org/10.1021/acs.biochem.6b01008.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Yoneyama-Hirozane M, Deguchi K, Hirakawa T, Ishii T, Odani T, Matsui J, et al. Identification and characterization of a new series of ghrelin O-acyl transferase inhibitors. SLAS Discov. 2018;23(2):154–63.  https://doi.org/10.1177/2472555217727097.CrossRefPubMedGoogle Scholar
  56. 56.
    Howick K, Griffin BT, Cryan JF, Schellekens H. From belly to brain: targeting the ghrelin receptor in appetite and food intake regulation. Int J Mol Sci. 2017;18(2).  https://doi.org/10.3390/ijms18020273.CrossRefGoogle Scholar
  57. 57.
    Lin L, Saha PK, Ma X, Henshaw IO, Shao L, Chang BH, et al. Ablation of ghrelin receptor reduces adiposity and improves insulin sensitivity during aging by regulating fat metabolism in white and brown adipose tissues. Aging Cell. 2011;10(6):996–1010.  https://doi.org/10.1111/j.1474-9726.2011.00740.x.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Veeraragavan K, Sethumadhavan K, Bowers CY. Growth hormone-releasing peptide (GHRP) binding to porcine anterior pituitary and hypothalamic membranes. Life Sci. 1992;50(16):1149–55.CrossRefGoogle Scholar
  59. 59.
    Lawrence CB, Snape AC, Baudoin FM, Luckman SM. Acute central ghrelin and GH secretagogues induce feeding and activate brain appetite centers. Endocrinology. 2002;143(1):155–62.  https://doi.org/10.1210/endo.143.1.8561.CrossRefPubMedGoogle Scholar
  60. 60.
    Bellone J, Ghizzoni L, Aimaretti G, Volta C, Boghen MF, Bernasconi S, et al. Growth hormone-releasing effect of oral growth hormone-releasing peptide 6 (GHRP-6) administration in children with short stature. Eur J Endocrinol. 1995;133(4):425–9.CrossRefGoogle Scholar
  61. 61.
    Ramirez VT, van Oeffelen W, Torres-Fuentes C, Chruscicka B, Druelle C, Golubeva AV, et al. Differential functional selectivity and downstream signaling bias of ghrelin receptor antagonists and inverse agonists. FASEB J. 2019;33(1):518–31.  https://doi.org/10.1096/fj.201800655R.CrossRefPubMedGoogle Scholar
  62. 62.
    Asakawa A, Inui A, Kaga T, Katsuura G, Fujimiya M, Fujino MA, et al. Antagonism of ghrelin receptor reduces food intake and body weight gain in mice. Gut. 2003;52(7):947–52.  https://doi.org/10.1136/gut.52.7.947.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Mosa R, Huang L, Li H, Grist M, LeRoith D, Chen C. Long-term treatment with the ghrelin receptor antagonist [d-Lys3]-GHRP-6 does not improve glucose homeostasis in nonobese diabetic MKR mice. Am J Physiol Regul Integr Comp Physiol. 2018;314(1):R71–r83.  https://doi.org/10.1152/ajpregu.00157.2017.CrossRefPubMedGoogle Scholar
  64. 64.
    Bowers CY, Tannenbau GS, Coy DH, Hocart SJ. Ghrelin/growth hormone releasing peptide/growth hormone secretatogue receptor antagonists and uses thereof. US Patent Application No. 010389 2007. https://patents.google.com/patent/WO2007127457A2/nl.
  65. 65.
    Demange L, Boeglin D, Moulin A, Mousseaux D, Ryan J, Berge G, et al. Synthesis and pharmacological in vitro and in vivo evaluations of novel triazole derivatives as ligands of the ghrelin receptor. J Med Chem. 2007;50(8):1939–57.  https://doi.org/10.1021/jm070024h.CrossRefPubMedGoogle Scholar
  66. 66.
    Moulin A, Demange L, Berge G, Gagne D, Ryan J, Mousseaux D, et al. Toward potent ghrelin receptor ligands based on trisubstituted 1,2,4-triazole structure. 2. Synthesis and pharmacological in vitro and in vivo evaluations. J Med Chem. 2007;50(23):5790–806.  https://doi.org/10.1021/jm0704550.CrossRefPubMedGoogle Scholar
  67. 67.
    Gomez JL, Ryabinin AE. The effects of ghrelin antagonists [D-Lys(3) ]-GHRP-6 or JMV2959 on ethanol, water, and food intake in C57BL/6J mice. Alcohol Clin Exp Res. 2014;38(9):2436–44.  https://doi.org/10.1111/acer.12499.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Salome N, Haage D, Perrissoud D, Moulin A, Demange L, Egecioglu E, et al. Anorexigenic and electrophysiological actions of novel ghrelin receptor (GHS-R1A) antagonists in rats. Eur J Pharmacol. 2009;612(1–3):167–73.  https://doi.org/10.1016/j.ejphar.2009.03.066.CrossRefPubMedGoogle Scholar
  69. 69.
    Torsello A, Bresciani E, Tamiazzo L, Bulgarelli I, Caporali S, Moulin A, et al. Novel potent and selective non-peptide ligands of ghrelin receptor: characterization of endocrine and extraendocrine actions. Endocr Abstr. 2008;16:P575.Google Scholar
  70. 70.
    Halem HA, Taylor JE, Dong JZ, Shen Y, Datta R, Abizaid A, et al. A novel growth hormone secretagogue-1a receptor antagonist that blocks ghrelin-induced growth hormone secretion but induces increased body weight gain. Neuroendocrinology. 2005;81(5):339–49.  https://doi.org/10.1159/000088796.CrossRefPubMedGoogle Scholar
  71. 71.
    Ueno S, Yoshida S, Mondal A, Nishina K, Koyama M, Sakata I, et al. In vitro selection of a peptide antagonist of growth hormone secretagogue receptor using cDNA display. Proc Nat Sci U S A. 2012;109(28):11121–6.  https://doi.org/10.1073/pnas.1203561109.CrossRefGoogle Scholar
  72. 72.
    Esler WP, Rudolph J, Claus TH, Tang W, Barucci N, Brown SE, et al. Small-molecule ghrelin receptor antagonists improve glucose tolerance, suppress appetite, and promote weight loss. Endocrinology. 2007;148(11):5175–85.  https://doi.org/10.1210/en.2007-0239.CrossRefPubMedGoogle Scholar
  73. 73.
    Longo KA, Govek EK, Nolan A, McDonagh T, Charoenthongtrakul S, Giuliana DJ, et al. Pharmacologic inhibition of ghrelin receptor signaling is insulin sparing and promotes insulin sensitivity. J Pharmacol Exp Ther. 2011;339(1):115–24.  https://doi.org/10.1124/jpet.111.183764.CrossRefPubMedGoogle Scholar
  74. 74.
    Rudolph J, Esler WP, O'Connor S, Coish PD, Wickens PL, Brands M, et al. Quinazolinone derivatives as orally available ghrelin receptor antagonists for the treatment of diabetes and obesity. J Med Chem. 2007;50(21):5202–16.  https://doi.org/10.1021/jm070071+.CrossRefPubMedGoogle Scholar
  75. 75.
    Hoveyda H, Marsault È, Thomas H, Fraser G, Beaubien S, Mathieu A et al. Macrocyclic ghrelin receptor antagonists and inverse agonists and methods of using the same. US Patent Application No. 0105389 2011 www.google.com/patents/US20110105389.
  76. 76.
    Els S, Beck-Sickinger AG, Chollet C. Ghrelin receptor: high constitutive activity and methods for developing inverse agonists. Methods Enzymol. 2010;485:103–21.  https://doi.org/10.1016/b978-0-12-381296-4.00006-3.CrossRefPubMedGoogle Scholar
  77. 77.
    Mokrosinski J, Holst B. Modulation of the constitutive activity of the ghrelin receptor by use of pharmacological tools and mutagenesis. Methods Enzymol. 2010;484:53–73.  https://doi.org/10.1016/b978-0-12-381298-8.00003-4.CrossRefPubMedGoogle Scholar
  78. 78.
    Holst B, Lang M, Brandt E, Bach A, Howard A, Frimurer TM, et al. Ghrelin receptor inverse agonists: identification of an active peptide core and its interaction epitopes on the receptor. Mol Pharmacol. 2006;70(3):936–46.  https://doi.org/10.1124/mol.106.024422.CrossRefPubMedGoogle Scholar
  79. 79.
    Els S, Schild E, Petersen PS, Kilian TM, Mokrosinski J, Frimurer TM, et al. An aromatic region to induce a switch between agonism and inverse agonism at the ghrelin receptor. J Med Chem. 2012;55(17):7437–49.  https://doi.org/10.1021/jm300414b.CrossRefPubMedGoogle Scholar
  80. 80.
    Holst B, Mokrosinski J, Lang M, Brandt E, Nygaard R, Frimurer TM, et al. Identification of an efficacy switch region in the ghrelin receptor responsible for interchange between agonism and inverse agonism. J Biol Chem. 2007;282(21):15799–811.  https://doi.org/10.1074/jbc.M609796200.CrossRefGoogle Scholar
  81. 81.
    • Ge X, Yang H, Bednarek MA, Galon-Tilleman H, Chen P, Chen M, et al. LEAP2 is an endogenous antagonist of the ghrelin receptor. Cell Metab. 2018;27(2):461–9.e6.  https://doi.org/10.1016/j.cmet.2017.10.016. This recent study reports the effects of an endogenous GHSR antagonist. CrossRefPubMedGoogle Scholar
  82. 82.
    M'Kadmi C, Cabral A, Barrile F, Giribaldi J, Cantel S, Damian M, et al. N-terminal liver-expressed antimicrobial peptide 2 (LEAP2) region exhibits inverse agonist activity toward the ghrelin receptor. J Med Chem. 2019;62(2):965–73.  https://doi.org/10.1021/acs.jmedchem.8b01644.CrossRefPubMedGoogle Scholar
  83. 83.
    Takahashi B, Funami H, Iwaki T, Maruoka H, Shibata M, Koyama M, et al. Orally active ghrelin receptor inverse agonists and their actions on a rat obesity model. Bioorg Med Chem. 2015;23(15):4792–803.  https://doi.org/10.1016/j.bmc.2015.05.047.CrossRefPubMedGoogle Scholar
  84. 84.
    Takahashi B, Funami H, Iwaki T, Maruoka H, Nagahira A, Koyama M, et al. 2-Aminoalkyl nicotinamide derivatives as pure inverse agonists of the ghrelin receptor. Bioorg Med Chem Lett. 2015;25(13):2707–12.  https://doi.org/10.1016/j.bmcl.2015.04.040.CrossRefPubMedGoogle Scholar
  85. 85.
    McCoull W, Barton P, Brown AJ, Bowker SS, Cameron J, Clarke DS, et al. Identification, optimization, and pharmacology of acylurea GHS-R1a inverse agonists. J Med Chem. 2014;57(14):6128–40.  https://doi.org/10.1021/jm500610n.CrossRefPubMedGoogle Scholar
  86. 86.
    Abegg K, Bernasconi L, Hutter M, Whiting L, Pietra C, Giuliano C, et al. Ghrelin receptor inverse agonists as a novel therapeutic approach against obesity-related metabolic disease. Diabetes Obes Metab. 2017;19(12):1740–50.  https://doi.org/10.1111/dom.13020.CrossRefPubMedGoogle Scholar
  87. 87.
    Bhattacharya SK, Andrews K, Beveridge R, Cameron KO, Chen C, Dunn M, et al. Discovery of PF-5190457, a potent, selective, and orally bioavailable ghrelin receptor inverse agonist clinical candidate. ACS Med Chem Lett. 2014;5(5):474–9.  https://doi.org/10.1021/ml400473x.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Cameron KO, Bhattacharya SK, Loomis AK. Small molecule ghrelin receptor inverse agonists and antagonists. J Med Chem. 2014;57(21):8671–91.  https://doi.org/10.1021/jm5003183.CrossRefPubMedGoogle Scholar
  89. 89.
    Kong J, Chuddy J, Stock IA, Loria PM, Straub SV, Vage C, et al. Pharmacological characterization of the first in class clinical candidate PF-05190457: a selective ghrelin receptor competitive antagonist with inverse agonism that increases vagal afferent firing and glucose-dependent insulin secretion ex vivo. Br J Pharmacol. 2016;173(9):1452–64.  https://doi.org/10.1111/bph.13439.CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    •• Denney WS, Sonnenberg GE, Carvajal-Gonzalez S, Tuthill T, Jackson VM. Pharmacokinetics and pharmacodynamics of PF-05190457: The first oral ghrelin receptor inverse agonist to be profiled in healthy subjects. Br J Clin Pharmacol. 2017;83(2):326–38.  https://doi.org/10.1111/bcp.13127. This is the first study testing an inverse agonist of the ghrelin receptor in humans showing inhibitory actions on growth hormone secretion, gastric emptying and postprandial glucose levels as well as safety and torability. CrossRefPubMedGoogle Scholar
  91. 91.
    Johansson S, Fredholm BB, Hjort C, Morein T, Kull B, Hu PS. Evidence against adenosine analogues being agonists at the growth hormone secretagogue receptor. Biochem Pharmacol. 2005;70(4):598–605.  https://doi.org/10.1016/j.bcp.2005.05.023.CrossRefPubMedGoogle Scholar
  92. 92.
    Hermansson NO, Morgan DG, Drmota T, Larsson N. Adenosine is not a direct GHSR agonist--artificial cross-talk between GHSR and adenosine receptor pathways. Acta Physiologica (Oxford, England). 2007;190(1):77–86.  https://doi.org/10.1111/j.1365-201X.2007.01691.x.CrossRefGoogle Scholar
  93. 93.
    NIH U. S National Library of Medicine ClinicalTrails.gov. https://clinicaltrials.gov/ct2/results?term=PF-05190457 Accessed 3 August 2019.

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Charité Center for Internal Medicine and DermatologyCharité Center for Internal Medicine and Dermatology, Department for Psychosomatic Medicine; Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of HealthBerlinGermany
  2. 2.Department of Psychosomatic Medicine and PsychotherapyMedical University Hospital TübingenTübingenGermany

Personalised recommendations